The present invention is concerned with novel indole and dihydroindole derivatives, their manufacture and their use as medicaments.
2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.) is required for the biosynthesis of cholesterol, ergosterol and other sterols. Causal risk factors that directly promote the development of coronary and peripheral atherosclerosis include elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), hypertension, cigarette smoking and diabetes mellitus. Other synergistic risk factors include elevated concentrations of triglyceride (TG)-rich lipoproteins, small, dense low-density lipoprotein particles, lipoprotein (a) (Lp(a)), and homocysteine. Predisposing risk factors modify the causal or conditional risk factors and thus affect atherogenesis indirectly. The predisposing risk factors are obesity, physical inactivity, family history of premature CVD, and male sex. The strong connection between coronary heart disease (CHD) and high LDL-C levels in plasma, and the therapeutic advantage of lowering elevated LDL-C levels are now well established (Gotto et al., Circulation 81, 1990, 1721-1733; Stein et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113-156; Illingworth, Med. Clin. North. Am. 84, 2000, 23-42). Cholesterol-rich, sometimes unstable, atherosclerotic plaques lead to the occlusion of blood vessels resulting in an ischemia or an infarct. Studies with respect to primary prophylaxis have shown that a lowering of plasma LDL-C levels in plasma reduces the frequency of non-fatal incidences of CHD, while the overall morbidity remains unchanged. The lowering of plasma LDL-C levels in patients with pre-established CHD (secondary intervention) reduces CHD mortality and morbidity; meta-analysis of different studies shows that this decrease is proportional to the reduction of the LDL-C (Ross et al., Arch. Intern. Med. 159, 1999, 1793-1802).
The clinical advantage of cholesterol lowering is greater for patients with pre-established CHD than for asymptomatic persons with hypercholesterolemia. According to current guidelines, cholesterol lowering treatment is recommended for patients who had survived a myocardial infarct or patients suffering from angina pectoris or another atherosclerotic disease, with a target LDL-C level of 100 mg/dl.
Preparations such as bile acid sequestrants, fibrates, nicotinic acid, probucol as well as statins, i.e. HMGxe2x80x94Coxe2x80x94A reductase inhibitors such as simvastatin and atorvastatin, are used for usual standard therapies. The best statins reduce plasma LDL-C effectively by at least 40%, and also plasma triglycerides, a synergistic risk factor, but less effectively. In contrast, fibratesreduce plasma triglycerides effectively, but not LDL-C. Combination of a statin and a fibrate proved to be very efficacious in lowering LDL-C and triglycerides (Ellen and McPherson, J. Cardiol. 81, 1998, 60B-65B), but safety of such a combination remains an issue (Shepherd, Eur. Heart J. 16, 1995, 5-13). A single drug with a mixed profile combining effective lowering of both LDL-C and triglycerides would provide additional clinical benefit to asymptomatic and symptomatic patients.
In humans, statins are well tolerated at standard dosage, but reductions in non-sterol intermediates in the cholesterol synthesis pathway, such as isoprenoids and coenzyme Q, may be associated with adverse clinical events at high doses (Davignon et al., Can. J. Cardiol. 8, 1992, 843-864; Pederson and Tobert, Drug Safety 14, 1996, 11-24).
This has stimulated the search for, and development of compounds that inhibit cholesterol biosynthesis, yet act distal to the synthesis of these important, non-sterol intermediates. 2,3-oxidosqualene:lanosterol cyclase (OSC), a microsomal enzyme, represents a unique target for a cholesterol-lowering drug (Morand et al., J. Lipid Res., 38, 1997, 373-390; Mark et al., J. Lipid Res. 37, 1996, 148-158). OSC is downstream of farnesyl-pyrophosphate, beyond the synthesis of isoprenoids and coenzyme Q. In hamsters, pharmacologically active doses of an OSC inhibitor showed no adverse side-effects, in contrast to a statin which reduced food-intake and body weight, and increased plasma bilirubin, liver weight and liver triglyceride content (Morand et al., J. Lipid Res., 38, 1997, 373-390). The compounds described in European Patent Application No. 636 367, which inhibit OSC and which lower the total cholesterol in plasma, belong to these substances.
OSC inhibition does not trigger the overexpression of HMGR because of an indirect, negative feed-back regulatory mechanism involving the production of 24(S),25-epoxycholesterol (Peffley et al., Biochem. Pharmacol. 56, 1998, 439-449; Nelson et al., J. Biol. Chem. 256, 1981, 1067-1068; Spencer et al., J. Biol. Chem. 260, 1985, 13391-13394; Panini et al., J. Lipid Res. 27, 1986, 1190-1204; Ness et al., Arch. Biochem. Biophys. 308, 1994, 420-425). This negative feed-back regulatory mechanism is fundamental to the concept of OSC inhibition because (i) it potentiates synergistically the primary inhibitory effect with an indirect down-regulation of HMGR, and (ii) it prevents the massive accumulation of the precursor monooxidosqualene in the liver. In addition, 24(S),25-epoxycholesterol was found to be one of the most potent agonists of the nuclear receptor LXR (Janowski et al., Proc. Natl. Acad. Sci. USA, 96, 1999, 266-271). Considering that 24(S),25-epoxycholesterol is a by-product of inhibition of OSC it is hypothesized that the OSC inhibitors of the present invention could also indirectly activate LXR-dependent pathways such as (i) cholesterol-7alpha-hydroxylase to increase the consumption of cholesterol via the bile acid route, (ii) expression of ABC proteins with the potential to stimulate reverse cholesterol transport and increase plasma HDL-C levels (Venkateswaran et al., J. Biol. Chem. 275, 2000, 14700-14707; Costet et al., J. Biol. Chem. June 2000, in press; Ordovas, Nutr Rev 58, 2000, 76-79, Schmitz and Kaminsky, Front Biosci 6, 2001, D505-D514), and/or inhibit intestinal cholesterol absorption (Mangelsdorf, XIIth International Symposium on Atherosclerosis, Stockholm, June 2000). In addition, possible cross talks between fatty acid and cholesterol metabolism mediated by liver LXR have been hypothesized (Tobin et al., Mol. Endocrinol. 14, 2000, 741-752).
The invention relates to compounds of the formula (I) 
wherein
the bond  between the carbon atom Ca and the carbon atom Cb is a single or a double bond,
U is O or a lone pair,
V is a) O, S, NR1, or CH2, and L is lower-alkylene or lower-alkenylene, b) xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and L is lower-alkylene or a single bond,
n is 0 to 7,
X is hydrogen or one or more optional halogen and/or lower-alkyl substituents,
A1 is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy, or thio-lower-alkoxy,
A2 is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, heterocyclyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy or thio-lower-alkoxy,
A3 and A4 independently from each other are hydrogen or lower-alkyl, or
A1 and A2 or A1 and A3 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 or
xe2x80x94A1xe2x80x94A3xe2x80x94 are lower-alkylene or lower-alkenylene, optionally substituted by R2, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 can optionally be replaced by NR3, S, or O,
A5 and A6 independently from each other are hydrogen or lower-alkyl,
A7 is alkyl with two or more carbon atoms, alkenyl, alkadienyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, or aryl-lower-alkyl,
R2 is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R4)R5), or lower-alkyl optionally substituted by hydroxy,
R1, R3, R4 and R5 independently from each other are hydrogen or lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
The compounds of formula I inhibit OSC and therefore also inhibit the biosynthesis of cholesterol, ergosterol and other sterols, and reduce the plasma cholesterol levels. They can therefore be used in the therapy and prophylaxis of hypercholesterolemia, hyperlipemia, arteriosclerosis and vascular diseases in general. Furthermore, they can be used in the therapy and/or prevention of mycoses, parasite infections, gallstones, cholestatic liver disorders, tumors and hyperproliferative disorders, e.g. hyperproliferative skin and vascular disorders. In addition, it has unexpectedly been found that the compounds of the present invention can also be of therapeutical use to improve glucose tolerance in order to treat and/or prevent related diseases such as diabetes. The compounds of the present invention further exhibit improved pharmacological properties compared to known compounds.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9clone pairxe2x80x9d refers to an unbound electron pair, in particular to the unbound electron pair of a nitrogen atom in e.g. an amine.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
The term xe2x80x9cprotecting groupxe2x80x9d refers to groups such as acyl, azoyl, alkoxycarbonyl, aryloxycarbonyl, or silyl. Examples are e.g. t-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl which can be used for the protection of amino groups or trimethylsilyl, dimethyl-tert.-butyl-silyl or tert.-butyl-diphenyl-silyl, which can be used for the protection of hydroxy groups, trityl or p-methoxybenzyl for sulfur, methyl or benzyl for the protection of phenole derivatives, methyl, ethyl or tert.-butyl for the protection of thiophenole derivatives.
The term xe2x80x9calkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl groups. Alkyl groups can be substituted e.g. with halogen, hydroxy, lower-alkoxy, thio-lower-alkoxy, lower-alkoxy-carbonyl, NH2, and/or N(lower-alkyl)2.
The term xe2x80x9clower-alkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. A lower-alkyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is an alkyl. The term xe2x80x9clower-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is a lower-alkyl. The term xe2x80x9cthio-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Sxe2x80x94, wherein Rxe2x80x2 is an alkyl. The term xe2x80x9cthio-lower-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Sxe2x80x94, wherein Rxe2x80x2 is a lower-alkyl.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 20, preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower-alkenyl groups as described below also are preferred alkenyl groups. The term xe2x80x9clower-alkenylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propenyl. An alkenyl or lower-alkenyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkadienylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising 2 olefinic bonds and up to 20, preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower-alkadienyl groups as described below also are preferred alkadienyl groups. The term xe2x80x9clower-alkadienylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising 2 olefinic bonds and up to 7 carbon atoms. An alkadienyl or lower-alkadienyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkinylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 20, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkinylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propinyl. An alkinyl or lower-alkinyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkylenexe2x80x9d refers to a straight chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms. The term xe2x80x9clower-alkylenexe2x80x9d refers to a straight chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 7, preferably 1 to 6 or 3 to 6 carbon atoms. Straight chain alkylene or lower-alkylene groups are preferred. An alkylene or lower-alkylene group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkenylenexe2x80x9d refers to a straight chain or branched divalent hydrocarbon group comprising an olefinic bond and up to 20 carbon atoms, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkenylenexe2x80x9d refers to a straight chain or branched divalent hydrocarbon group comprising an olefinic bond and up to 7, preferably up to 5, C-atoms. Straight chain alkenylene or lower-alkenylene groups are preferred. An alkenylene or lower-alkenylene group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9carylxe2x80x9d relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted by lower-alkyl, lower-alkinyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, cyano, CF3, NH2, N(lower-alkyl)2, aminocarbonyl, carboxy, nitro, lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl, lower-alkylcarbonyloxy, aryl, and/or aryloxy. Preferred substituents are halogen, CF3, lower-alkyl, lower-alkinyl, and/or phenyl. More preferred substituents are fluorine, chlorine, bromine and CF3.
The term xe2x80x9cheterocyclylxe2x80x9d as used herein denotes optionally substituted aromatic or non-aromatic monocyclic heterocycles with 5 or 6 ring members, which comprise 1, 2 or 3 hetero atoms selected from nitrogen, oxygen and sulfur. Examples of suitable heterocycles are furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-thiazolyl. A heterocyclyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9carylxe2x80x9d. An example of a heterocyclyl group having a substituent is 2-methyl-pyrimidinyl.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. Preferred salts are formates, hydrochlorides, hydrobromides and methanesulfonic acid salts.
The term xe2x80x9cpharmaceutically acceptable estersxe2x80x9d embraces esters of the compounds of formula (I), in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as sulphuric acid, nitric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
In detail, the present invention relates to compounds of formula (I) 
wherein
the bond  between the carbon atom Ca and the carbon atom Cb is a single or a double bond,
U is O or alone pair,
V is a) O, S, NR1, or CH2, and L is lower-alkylene or lower-alkenylene, b) xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and L is lower-alkylene or a single bond,
n is 0 to 7,
X is hydrogen or one or more optional halogen and/or lower-alkyl substituents,
A1 is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy, or thio-lower-alkoxy,
A2 is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, heterocyclyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy or thio-lower-alkoxy,
A3 and A4 independently from each other are hydrogen or lower-alkyl, or
A1 and A2 or A1 and A3 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 or
xe2x80x94A1xe2x80x94A3xe2x80x94 are lower-alkylene or lower-alkenylene, optionally substituted by R2, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 can optionally be replaced by NR3, S, or O,
A5 and A6 independently from each other are hydrogen or lower-alkyl,
A7 is alkyl with two or more carbon atoms, alkenyl, alkadienyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, or aryl-lower-alkyl,
R2 is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R4,R5), or lower-alkyl optionally substituted by hydroxy,
R1, R3, R4 and R5 independently from each other are hydrogen or lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Preferred are compounds of formula (I) and/or pharmaceutically acceptable salts thereof. Other preferred embodiments relate to compounds of formula (I) wherein U is a lone pair or to compounds of formula (I) wherein U is O.
Each of the definitions of V given above, a) and b), individually constitutes a preferred embodiment of the present invention. Compounds as described above in which V is O or CH2 and L is lower-alkylene relate to a further preferred embodiment of the present invention. Further preferred compounds are those wherein V is O and L is lower-alkenylene. Other preferred compounds are those, wherein V is xe2x80x94Cxe2x89xa1Cxe2x80x94 and L is lower-alkylene or a single bond. Compounds as described above, wherein n is 0 also relate to a preferred embodiment of the present invention. It is preferred that in L and (CH2)n together there are not more than 10 carbon atoms, preferably not more than 7, more preferably not more than 5.
Other preferred compounds of the present invention are those in which A1 represents hydrogen or lower-alkyl optionally substituted with hydroxy, preferably those in which A1 is methyl, or ethyl optionally substituted with hydroxy. Another group of preferred compounds of the present invention are those in which A2 represents cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, or lower-alkyl optionally substituted by hydroxy or lower-alkoxy, with those compounds wherein A2 represents lower-alkenyl, or lower-alkyl optionally substituted by hydroxy being more preferred, and with those compounds wherein A2 represents methyl, ethyl, 2-hydroxy-ethyl, n-propyl, or 2-propenyl being especially preferred. In compounds wherein A2 can be heterocyclyl, such a heterocyclyl group preferably is pyridinyl, 2-methyl-pyrimidinyl, 4,5-dihydro-oxazolyl or 4,5-dihydro-thiazolyl. Other preferred compounds are those wherein A2 represents pyridinyl, 2-methyl-pyrimidinyl, 4,5-dihydro-oxazolyl or 4,5-dihydro-thiazolyl, preferably pyridin-4-yl.
Compounds of formula (I), wherein A1 and A2 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 is lower-alkylene or lower-alkenylene, optionally substituted by R2, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 can optionally be replaced by O, wherein R2 is hydroxy are also preferred, with those compounds wherein xe2x80x94A1xe2x80x94A2xe2x80x94 is xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94 being particularly preferred. In compounds wherein A1 and A2 are bonded to each other to form a ring, said ring is preferably a 4-, 5-, or 6-membered ring such as e.g. piperidinyl or pyrrolidinyl.
A further preferred embodiment of the present invention relates to compounds of formula (I), wherein A3 and/or A4 represent hydrogen. Further preferred compounds are those wherein A3 is methyl and/or those wherein A4 is methyl. Other preferred compounds are those, wherein A5 is hydrogen or methyl, preferably hydrogen, and/or wherein A6 is hydrogen or methyl, preferably hydrogen.
Compounds of formula (I), wherein A7 is alkenyl, particularly lower-alkenyl, alkadienyl, particularly lower-alkadienyl, aryl, or aryl-lower-alkyl represent a preferred embodiment of the present invention. Other preferred compounds are those in which A7 is phenyl or benzyl, optionally substituted by 1 to 3 substituents independently selected from the group concisting of fluorine, chlorine, bromine, CF3, ethyl, ethinyl, and phenyl, with those compounds wherein A7 is 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, or 4-trifluoro-phenyl being particularly preferred. A7 may not be methyl. Another preferred group relates to compounds wherein X is hydrogen. Other preferred compounds are those wherein X is fluorine.
A further preferred embodiment of the present invention relates to those compounds as defined above wherein the bond  between the carbon atom Ca and the carbon atom Cb is a double bond.
Further preferred compounds of formula (I) as defined above are those, wherein the bond  between the carbon atom Ca and the carbon atom Cb is a single or a double bond,
U is O or a lone pair,
V is a) O, S, NR1, or CH2, and L is lower-alkylene or lower-alkenylene, b) xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and L is lower-alkylene or a single bond,
n is 0 to 7,
X is hydrogen or one or more optional halogen and/or lower-alkyl substituents,
A1 is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy, or thio-lower-alkoxy,
A2 is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy or thio-lower-alkoxy,
A3 and A4 independently from each other are hydrogen or lower-alkyl, or
A1 and A2 or A1 and A3 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 or
xe2x80x94A1xe2x80x94A3xe2x80x94 are lower-alkylene or lower-alkenylene, optionally substituted by R2, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 can optionally be replaced by NR3, S, or O,
A5 and A6 independently from each other are hydrogen or lower-alkyl,
A7 is alkyl with two or more carbon atoms, alkenyl, alkadienyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, or aryl-lower-alkyl,
R2 is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R4,R5), or lower-alkyl optionally substituted by hydroxy,
R1, R3, R4 and R5 independently from each other are hydrogen or lower-alkyl,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Still more preferred embodiments of the invention are those of general formula (VII) 
wherein
the bond  between the carbon atom Ca and the carbon atom Cb is a single or a double bond;
V is a) O or CH2 and L is lower-alkylene or lower-alkenylene or b) xe2x80x94Cxe2x89xa1Cxe2x80x94 and L is lower-alkylene or a single bond;
X is hydrogen or one or more halogen substituents;
A1 is hydrogen, lower-alkyl or lower-alkoxy, and A2 is cycloalkyl, lower-alkenyl, lower-alkinyl, heterocyclyl or lower-alkyl optionally substituted by hydroxy, cycloalkyl or lower-alkoxy, or
A1 and A2 are bonded to each other to form lower alkenylene, lower alkylene substituted by OH or lower alkylene in which one xe2x80x94CH2xe2x80x94 group is optionally substituted by O;
A3, A4, A5 and A6 are hydrogen or lower-alkyl; and
A7 is phenyl or lower alkyl phenyl, wherein the phenyl group is optionally substituted with halogen, phenyl, alkyl, alkinyl or trifluoromethyl; and pharmaceuticaly acceptable salts and esters thereof.
Preferred compounds of general formula (VII) are those selected from the group consisting of
Cyclopropyl-{6-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-hexyl}-methyl-amine,
Allyl-{6-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-hexyl}-methyl-amine,
1-(4-Fluoro-phenyl)-5-(6-piperidin-1-yl-hexcyloxy)-1H-indole,
Allyl-{7-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-heptyl}-methyl-amine,
1-(4-Fluoro-phenyl)-5-(7-piperidin-1-yl-heptyloxy)-1H-indole, Allyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
{6-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxyl]-hexyl}-methyl-propyl-amine,
Allyl-{5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine,
2-(Ethyl-{5-[1-(4-fluoro-phenyl)-1H-indol -5-yl]-pent-4-ynyl}-amino)-ethanol,
Allyl-{5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine,
2-(Ethyl-{5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentylyl}-amino)-ethanol,
{4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine,
Allyl-{6-[1-(4-fluoro-phenyl)-2,3-dihydro-1H-indol-5-yloxy]-hexyl}-methyl-amine,
2-(Ethyl-{6-[1-(4-fluoro-phenyl)-2,3-dihydro-1H-indol-5-yloxy]-hexyl}-amino)-ethanol,
Allyl-{4-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
Allyl-{5-[1-(4-chloro-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine,
Allyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-propyl}-methyl-amine,
{4-[1-(4-Bromo-phenyl)-2,3-dihydro-1H-indol-5-yloxy]-butyl}-diethyl-amine,
{4-[1-(2-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine, {4-[1-(3-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine,
[4-(1-Biphenyl-2-yl-1H-indol-5-yloxy, -butyl]-diethyl-amine,
Allyl-{5-[1-(2-bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine,
Allyl-{5-[1-(3-bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine,
Allyl-[5-(1-biphenyl-2-yl-1H-indol-5-yl)-pentyl]-methyl-amine,
{4-[1-(4-Bromo-benzyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine,
Allyl-methyl-{5-[1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl]-pentyl}-amine,
Allyl-methyl-[6-(1-phenyl-1H-indol-5-yloxy)-hexyl]-amine,
Diethyl-[6-(1-phenyl-1H-indol-5-yloxy)-hexyl]-amine,
2-{Ethyl-[6-(1-phenyl-1H-indol-5-yloxy)-hexyl]-amino}-ethanol,
Allyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amine,
2-(Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amino)-ethanol,
Diethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amine,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-dimethyl-amine,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,
2-({4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amino)-ethanol,
2-[{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,
Cyclopropylmethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
1-(4-Fluoro-phenyl)-5-(4-pyrrolidin-1-yl-butoxy)-1H-indole,
Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amine,
1-(4-Fluoro-phenyl)-5-(4-morpholin-4-yl-butoxy)-1H-indole,
2-{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butylamino}-ethanol,
Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-(2-methoxy-ethyl)-amine,
1-{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-piperidin-4-ol,
5-[4-(3,6-Dihydro-2H-pyridin-1-yl)-butoxy]-1-(4-fluoro-phenyl)-1H-indole,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-propyl-amine,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-prop-2-ynyl-amine,
1-(4-Fluoro-phenyl)-5-(4-piperidin-1-yl-butoxy)-1H-indole,
5-(4-Azetidin-1-yl-butoxy)-1-(4-fluoro-phenyl)-1H-indole,
Allyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-amine,
Allyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-methyl-amine,
2-(Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-amino)-ethanol,
Diethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-amine,
{3-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-dimethyl-amine,
{3-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine,
2-({3-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-methyl-amino)-ethanol,
2-[{3-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanol,
Cyclopropylmethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-methyl-amine,
1-(4-Fluoro-phenyl)-5-(3-pyrrolidin-1-yl-propoxy)-1H-indole,
Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-amine,
1-(4-Fluoro-phenyl)-5-(3-morpholin-4-yl-propoxy)-1H-indole,
2-{3-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-propylamino}-ethanol,
Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-(2-methoxy-ethyl)-amine,
1-{3-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-piperidin-4-ol,
5-[3-(3,6-Dihydro-2H-pyridin-1-yl)-propoxy]-1-(4-fluoro-phenyl)-1H-indole,
{3-[1-(4-Fluoro-phenyl)-1-indol-5-yloxy]-propyl}-methyl-propyl-amine,
{3-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-propyl}-methyl-prop-2-ynyl-amine,
1-(4-Fluoro-phenyl)-5-(3-piperidin-1-yl-propoxy)-1H-indole,
5-(3-Azetidin-1-yl-propoxy)-1-(4-fluoro-phenyl)-1H-indole,
Allyl-{4-[1-(4-bromo-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
{4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-propyl-amine,
2-[{4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,
2-({4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-ethyl-amino)-ethanol,
{4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,
5-(4-Azetidin-1-yl-butoxy)-1-(4-bromo-phenyl)-1H-indole,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-propyl-amine,
2-({5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-ethyl-amino)-ethanol,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-dimethyl-amine,
2-({5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanol,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-methyl-amine,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-diethyl-amine,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-propyl-amine,
2-({5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pentyl}-ethyl-amino)-ethanol,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pentyl}-dimethyl-amine,
2-({5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amino)-ethanol,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pentyl}-(2-methoxy-ethyl)-methyl-amine,
{5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pentyl}-diethyl-amine,
2-(Ethyl-{5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol,
2-(Ethyl-{5-[1-(4-ethyl-phenyl)-1H-indol-5-yl]-pentyl}-amino)-ethanol,
Diethyl-{5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amine,
Diethyl-{5-[1-(4-ethyl-phenyl)-1H-indol-5-yl]-pentyl}-amine,
2-({5-[1-(4-Ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanol, and
2-({5-[1-(4-Ethyl-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amino)-ethanol,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Other preferred compounds of general formula (I) are those selected from the group consisting of
2-(Ethyl-{5-[1-(4-fluoro-phenyl)-3-methyl-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol,
2-(Ethyl-{5-[1-(4-fluoro-phenyl)-3-methyl-1H-indol-5-yl]-pentyl}-amino)-ethanol,
Allyl-{5-[1-(4-bromo-phenyl)-3-methyl-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine,
Allyl-methyl-{5-[3-methyl-1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amine,
Allyl-{4-[1-(4-bromo-phenyl)-2-methyl-1H-indol-5-yloxy]-butyl}-methyl-amine,
Allyl-methyl-{4-[2-methyl-1-(4-trifluoromethyl-phenyl)-1H-indol-5-yloxy]-butyl}-amine,
Allyl-methyl-{4-[2-methyl-1-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indol-5-yloxy]-butyl}-amine,
Allyl-{4-[2,3-dimethyl-1-(4-trifluoromethyl-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
Allyl-{4-[1-(4-bromo-phenyl)-2,3-dimethyl-1H-indol-5-yloxy]-butyl}-methyl-amine,
2-(Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-1,1-dimethyl-prop-2-ynyl}-amino)-ethanol,
1-(4-Fluoro-phenyl)-5-(3-methyl-3-piperidin-1-yl-but-1-ynyl)-1H-indole,
2-({3-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-1,1-dimethyl-prop-2-ynyl}-methyl-amino)-ethanol,
2-(Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-prop-2-ynyl}-amino)-ethanol,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
Allyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-but-2-enyl}-methyl-amine,
2-(Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-but-2-enyl}-amino)-ethanol,
Allyl-{4-[1-(4-chloro-phenyl)-6-fluoro-1H-indol-5-yloxyl]-butyl}-methyl-amine,
Allyl-{4-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
2-({4-[1-(4-Chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-methyl-amino)-ethanol,
2-({4-[6-Fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amino)-ethanol,
2-({4-[1-(4-Chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-ethyl-amino)-ethanol,
2-(Ethyl-{4-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amino)-ethanol,
Allyl-{5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine,
2-({5-[6-Fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-ethyl-amino)-ethanol,
Allyl-{4-[1-(4-chloro-phenyl)-6-fluoro-2,3-dihydro-1H-indol-5-yloxy]-butyl}-methyl-amine,
(4,5-Dihydro-oxazol-2-yl)-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
(4,5-Dihydro-thiazol-2-yl)-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-pyridin-4-yl-amine,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-pyridin-3-yl-amine,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-pyridin-2-yl-amine, and
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-(2-methyl-pyrimidin-4-yl)-amine,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Still more preferred embodiments of the invention are those of general formula (VIII) 
wherein
the bond  between the carbon atom Ca and the carbon atom Cb is a single or a double bond;
V is a) O or CH2 and L is lower-alkylene or lower-alkenylene or b)xe2x80x94Cxe2x89xa1Cxe2x80x94 and L is lower-alkylene or a single bond;
X is hydrogen or one or more halogen substituents;
Z is halogen or trifluoromethyl;
A1 is lower-alkyl or lower-alkoxy, and A2 is lower-alkyl, lower alkoxy, lower-alkenyl or a heterocyclyl having a single N hetero atom, or
A1 and A2 are bonded to each other to form lower-alkylene in which one xe2x80x94CH2xe2x80x94 group is optionally substituted by O; and
A3, A4, A5 and A6 are hydrogen or lower-alkyl; and
pharmaceutically acceptable salts and esters thereof.
Particularly preferred compounds of general formula (VIII) are those selected from the group consisting of
Allyl-{6-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-hexyl}-methyl-amine,
2-(Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amino)-ethanol,
1-(4-Fluoro-phenyl)-5-(4-morpholin-4-yl-butoxy)-1H-indole,
Diethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amine,
2-({4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-ethyl-amino)-ethanol,
Allyl-{5-[1-(4-chloro-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine,
2-[{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-propyl-amine,
Allyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
Allyl-{6-[1-(4-fluoro-phenyl)-2,3-dihydro-1H-indol-5-yloxy]-hexyl}-methyl-amine, and
2-(Ethyl-{5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentyl}-amino)-ethanol,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Other particularly preferred compounds of general formula (VIII) are those selected from the group consisting of
Allyl-{5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine,
and pharmaceutically acceptable salts thereof.
Other particularly preferred compounds of general formula (VIII) are those selected from the group consisting of
2-({4-[1-(4-Chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-ethyl-amino)-ethanol,
{4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-pyridin-4-yl-amine,
2-({4-[1-(4-Chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-methyl-amino)-ethanol,
2-(Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-but-2-enyl}-amino)-ethanol,
Allyl-{5-[1-(4-bromo-phenyl)-3-methyl-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine,
2-(Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-1,1-dimethyl-prop-2-ynyl}-amino)-ethanol,
2-(Ethyl-{5-[1-(4-fluoro-phenyl)-3-methyl-1H-indol-5-yl]-pentyl}-amino)-ethanol,
Allyl-methyl-{5-[3-methyl-1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amine,
Allyl-{4-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine,
2-({4-[6-Fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amino)-ethanol,
2-(Ethyl-{4-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-amino)-ethanol, and
2-(Ethyl-{5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Compounds of formula (I) can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers or as racemats. The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
The present invention also relates to a process for the manufacture of compounds as described above, which process comprises
reacting a compound of formula (II) 
with a compound (A1,A2,U)Nxe2x80x94C(A3,A4)xe2x80x94Lxe2x80x94M, wherein V is O, S or NR1, M is mesylate, tosylate, triflate, Cl, Br or I, P is A7 or a protecting group, and U, A1, A2, A3, A4, A5, A6, A7, X, L, n, R1 and the bond  between the carbon atom Ca and the carbon atom Cb have the significances given above, or wherein HV is mesylate, tosylate, Cl, Br or I, and M is OH, SH or NHR1, and R1 has the significance given above,
or b) reacting a compound of formula (III) 
with a compound NHA1,A2, wherein M is mesylate, tosylate, trifiate, Cl, Br or I, P is A7 or a protecting group, and A1, A2, A3, A4, A5, A6, A7, L, V, X, n and the bond  between the carbon atom Ca and the carbon atom Cb are as defined above,
or c) reacting a compound of formula (IV) 
with a compound (A1,A2,U)Nxe2x80x94C(A3,A4)xe2x80x94Lxe2x80x94Cxe2x89xa1CH, wherein M is Cl, Br, I or F3CO2SO, P is A7 or a protecting group, and U, A1, A2, A3, A4, A5, A6, A7, U, L, X and the bond  between the carbon atom Ca and the carbon atom Cb are as defined above,
or d) reacting a compound of formula (V) 
with a compound (A1,A2,U)Nxe2x80x94C(A3,A4)xe2x80x94Lxe2x80x94M, wherein M is mesylate, tosylate, triflate, Cl, Br or I, P is A7 or a protecting group, and A1, A2, A3, A4, A5, A6, A7, U, L, X, n and the bond  between the carbon atom Ca and the carbon atom Cb are as defined above,
or e) hydrogenating a compound of formula (VI) 
wherein V is xe2x80x94Cxe2x89xa1Cxe2x80x94, P is A7 or a protecting group, and A1, A2, A3, A4, A5, A6, A7, U, L, X and n are as defined above,
and optionally removing the protecting group P and introducing group A7,
and optionally converting a compound of formula (I) as defined above to a pharmaceutically acceptable salt,
and optionally converting a compound of formula (I) as defined above, wherein U is a lone pair, to a corresponding compound wherein U is O.
Preferred processes as described above are those, in which P is A7.
The invention further relates to compounds of formula (I) as defined above, when manufactured according to a process as defined above.
As described above, the compounds of formula (I) of the present invention can be used for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections and gallstones, and/or treatment and/or prophylaxis of impaired glucose tolerance, diabetes, tumors and/or hyperproliferative disorders, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Hyperproliferative skin and vascular disorders particularly come into consideration as hyperproliferative disorders.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
Further, the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.
In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia, which method comprises administering a compound as defined above to a human being or animal.
The invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.
In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Such medicaments comprise a compound as defined above.
The compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the examples or by methods known in the art, e.g. by methods described in: Richard J. Sundberg Indoles (Best Synthetic Methods), Series Editor A. R. Katritzky, O. Meth-Cohn, C. W. Rees, Acedemic Press, San Diego 1996, or inHouben-Weyl Methoden der Organischen Chemie, R. P. Kreker, Ed., Georg Thieme Verlag, Stuttgart, 1994, Bd E 6a,6b, or in Takeda, A.; Kamijo, S.; Yamamoto*, Y. Journal Amercian Chemical Society 2000, 122, 5662-63. and references cited therein. 
In scheme 1, the preparation of compounds of the present invention in which V is O, S or NR1 is outlined. Indole derivative 2 might be derived from a suitable protected indole derivative 1 by N-arylation by treatment e.g. with A) Cu, KOH and the desired halo-benzene derivative, or with B) fluorobenzene derivatives, 18-crown-6, KF on alox in DMSO (analogously to William J. Smith III, J. Scott Sawyer, Tetrahedron Letters 1999, Vol.37, No.3, 299-302.) or C) by palladium catalysized N-arylation (see David W. Old, Michele C. Harris, Stephen L. Buchwald Organic Letters 2000, 2,10,1403-1406.), D) CuI, ZnO, K2CO3, halobenzene (see Jens Perregaard et. al. J. Med. Chem. 1992, 35, 4813-4822.). For other N-substituted indoles A7 may be introduced by treatment with NaH and the corresponding electrophile in THF or DMF (step a). In the cases, in which a protecting group like BOC is introduced first, the indole derivative 1 can be treated with potassium tert. butylate followed by di-tert.-dibutylcarbonate in solvents such as DMF or THF (step a). If desired the indole system can be reduced to the corresponding indoline derivative 2 for example by employing NaCNBH3 in TFA (step b).
Furthermore, for the formation of the indoline compound 2 the reduction (e.g. with NaCNBH3) might be performed prior to introducing a protecting group for the nitrogen (e.g.PG2=BOC) or before introducing the moiety A7.
V-Deprotection might be achieved, in the case of 5-benzyloxyindole derivatives or 5-benzyloxyindoline 2 by hydrogenation with e.g. Pd/C in solvents like methanol or ethyl acetate, in the case of 5-methoxy-indole derivatives 2 by treatment for example with lithium-tri-sec-butylborohydride in THF. For V=S, NR1 or V=O and n greater than 0, deprotection using procedures known in the art (step c) gives the free HV-building block 3.
Alkylation of the phenol/thiophenol 3 (V=O, S, n=0) is accomplished in solvents such as acetone, DMF, DMA with K2CO3 and a suitable dihaloalkane or dihaloalkene (halogene is here represented by bromine, but can also be chlorine or iodine. It is also possible to use mesylates, tosylates or triflates instead of halogenides) at 0xc2x0 C. to reflux to yield halogenide 4 (step d). For the preparation of derivatives 4 (V=O, n greater than 0), the alcohol 3 can be treated with xcex1,xcfx89-dihaloalkanes or xcex1,xcfx89-dihaloalkenes under phase transfer conditions e.g. xcex1,xcfx89-dihaloalkanes/dihaloalkenes, NaOH, nBu4NHSO4. For V=S, O or NR1, the derivative 3 may be treated with xcex1,xcfx89-dihaloalkane in the presence of NaH in DMF 0xc2x0 C. to RT to yield bromide 4. For shorter alkanes (methyl, ethyl), the method of choice is the in situ generation of the haloalkane-triflate (from the corresponding haloalkanol with trifluoromethansulfonic anhydride/2,6-di-tert-butylpyridine in CH2Cl2 at 0xc2x0 C.). This haloalkane-triflate may then be reacted with 3 in the presence of a base such as 2,6-di-tert-butylpyridine in nitromethane at 60xc2x0 C. to yield bromide 4 [analogously to a procedure of Belostotskii, Anatoly M.; Hassner, Alfred. Synthetic methods. 41. Etherification of hydroxysteroids via triflates. Tetrahedron Lett. (1994), 35(28), 5075].
Compound 4 can be converted to the amine 5 or 6 with an excess of the corresponding amine NHA1A2 in a suitable solvent such as DMA, DMF, MeOH at RT or at 50-65xc2x0 C. or with amine NHA1A2, sodium hydride in DMF, DMA or THF. (step e). Compound 5 might be N-deprotected using basic conditions like aqueous NaOH in an alkohol for the indole derivatives or by treatment with TFA in CH2Cl2 at RT or reflux for the indoline derivatives. Introduction of the moiety A7 may be accomplished as described for step a to give compound 6.
Furthermore a conversion of the indoline derivative to the indole compound is possible e.g. using a halobenzene in DMSO in the presence of K2CO3 and CuI at elevated temperature.
Alternatively, the compound 3 may be transferred to the amine 6 or 8 by attaching the pre-assembled fragment A1A2NC(A3A4)LV-OMes/halogenide, which can be synthesised by known methods (shown e.g. in Scheme 2), using alkylating conditions (step i). Heteroaromate 3 (V=O, n greater than 0) can also be mesylated 3 (V=OMes) and then reacted with A1A2NC(A3A4)L-VH (synthesis described Scheme 2) in e.g. DMF with NaH as base to give 6 or 8 (with V=O, S, NR1). Compound 8 can be converted to 6 as described earlier for the conversion of derivative 5 to 6.
If A2=H, heterocyclic moieties A2 may be introduced by treatment with halo heterocycles in the presence of Huenig""s base in DMF (Ger. Offen. (1990), DE3905364 Al). Alternatively, Buchwald conditions e.g. Pd(OAc)2, 2-(Dicyclohexylphosphino) biphenyl, NaOtBu in toluene might be applied (John P. Wolfe, Hiroshi Tomori, Joseph P. Sadighi, Jingjun Yin, and Stephen L. Buchwald, J. Org. Chem., 65 (4), 1158-1174, 2000). For the preparation of oxazoline or thiaoxazolines the amine maybe treated with chloroethylisocyanate or chloroethylthioisocyanate in THF, followed by treatment with a base such as triethylamine or ammonium hydroxide (George R. Brown, David M. Hollinshead, Elaine S. E. Stokes, David Waterson, David S. Clarke, Alan J. Foubister, Steven C. Glossop, Fergus McTaggart, Donald J. Mirrlees, Graham J. Smith, and Robin Wood Journal of Medicinal Chemistry, 2000, 43, 26, 4964-72.).
Furthermore, the indole moiety of amine 6 may be reduced to indoline 6 using sodium cyanoborohydride as described for compound 2 (see above, step b).
Amine 6 maybe converted to a salt or to the N-oxide 7 (step h). For N-oxide 7 (V=O) a mixture of hydrogen peroxide urea adduct and phthalic anhydride in CH2Cl2 at RT may be used. For the preparation of the N-oxides 7 (V=S or NR1) an alternative route has to be employed (step k): Oxidation of the pre-assembled fragment A1A2NC(A3A4)L-OMes/halogenide to the corresponding N-oxide derivative, followed by alkylation of the compound 3 to give compound 7 or 9. Compound 9 may be transferred to 7 as described above for compound 5 by cleavage of the protecting group and introduction of A7.
For an amine 6 or for compounds 2 or 3 in which A7 is a halo- or hydroxy-substituted aromatic system (in case of the later, the corresponding triflate may be synthesized) the corresponding alkyne, alkyl, alkene, amine, alkoxy or thioalkoxy substituted A7 derivative can be synthesized employing Sonogashira reaction or palladium catalyzed amination, Cxe2x80x94O or Cxe2x80x94S coupling reactions. For the Sonogashira reaction, the arylhalogenide or aryltriflate may be treated with a suitable alkyne or alkynol in THF in the presence of a base such as triethylamine or piperidine with a catalytic amount of e.g. Pd(PPh3)4/CuI or Pd(OAc)2/CuI or PdCl2(PPh3)2/CuI at 45xc2x0 C. to 80xc2x0. These alkynes can then be reduced selectively. The introduction of an amine moiety may be achieved using primary or secondary amines and the arylhalogenide or aryltriflate using methods developed by Buchwald e.g. tris(Dibenzylideneacetone)dipalladium, 2(di-tertbutylphosphino)Biphenyl in toluene and Natrium tert-butylat as base to give the resulting substituted 2,3 or 6 [e.g. Wolfe, John P.; Tomori, Hiroshi; Sadighi, Joseph P.; Yin, Jingjun; Buchwald, Stephen L. Simple, efficient catalyst system for the palladium-catalyzed amination of aryl chlorides, bromides, and triflates. J. Org. Chem. (2000), 65(4), 1158-1174]. Other compounds with substituted A7 groups can e.g. be prepared according to the methods described in Palucki, Michael; Wolfe, John P.; Buchwald, Stephen L. Palladium-Catalyzed Intermolecular Carbon-Oxygen Bond Formation: A New Synthesis of Aryl Ethers. J. Am. Chem. Soc. (1997), 119(14), 3395-3396.
The resulting substituted amines 6 can then be transformed to compounds 7.
Scheme 2 shows the synthesis of amino-VH sidechain 13 that may be used for the synthesis of compounds with the corresponding V-spacers (V=NR1, S, or O). xcex1,xcfx89-dihalo-alkane, mesyl-alkanyl-halogenide, xcex1,xcfx89-dihaloalkene or mesyl-alkenyl-halogenide 10 may be treated with a suitable protected amine (HNR1-PG, PG=protecting group, e.g. BOC) in DMA or a thiol (HS-PG e.g., triphenylmethanethiol) in the presence of NaH in DMA to give the compound 11 (step a). Treatment with the amine A1A2NH yields the S- or N-protected amine 12 (step b) or in the case of xcex1,xcfx89-halo-alkanol or xcex1,xcfx89-haloalkenol 10 directly amino-alcohol 13. N-deprotection with procedures known in the art e.g. TFA in CH2Cl2 gives the amine side chain 13 (step c). The deprotection of the thiol moiety in 12 may be achieved with TFA/triisopropylsilane in CH2Cl2 at 0xc2x0 C. to RT to yield the aminothiol 13 (step c). Aminoalkanol 13 can be transformed further to mesylate 14 (step d).
In Scheme 3, the preparation of compounds of formula 7, in which V represents xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94 is outlined. The starting material is 5-hydroxyindol or 5-hydroxydihydroindol derivative 3, which may be transformed to the triflate 15a in pyridine with trifluoromethanesulfonic anhydride at 0xc2x0 C. to RT (step a). Sonogashira-coupling (step b) of the triflate 15a and a suitable alkynol or alkynechloride in piperidine with Pd(PPh3)4/CuI at 45xc2x0 C. to 80xc2x0 C. in analogy to a literature procedure yields alcohol 16a or chloride 16b [Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672.]. In case of A7=Bromo or Iodo-substituted aromatic system, triflate 15 is dissolved in THF with PdCl2(PPh3)2 as catalyst and alkynol or alkynechloride, triphenylphosphine, triethylamine and a catalytic amount of CuI to give alkyne 16a or 16b.
Alternatively, the alkynes 16a or 16b can be prepared by Sonogashira reaction of the 5-bromo-indol derivatives 15b with the corresponding alkynols or alkynechlorides.
Mesylation of alcohol 16a with methanesulfonylchloride e.g. in pyridine with DMAP (reaction step c) and subsequent amination (reaction step d) of the resulting mesylate 17 with a suitable amine NHA1A2 in a solvent like DMA, DMF or MeOH at RT or at 50-65xc2x0 C. optionally in the presence of a base such as Huenig""s base, NEt3, pyridine yields the amine 6. Alcohol 16a can also be treated with trifluoromethane sulfonic acid anhydride and Huenig""s base at xe2x88x9215xc2x0 C. in CH2Cl2 (in situ generation of the corresponding triflate) followed by treatment with the corresponding amine NHA1A2 at xe2x88x9215xc2x0 C. to RT. This is especially the method of choice for but-3-yn-1-ol-derivatives 16a. Chloride 16b can be transformed directly or via iodide (Finkelstein reaction) to the amine 6, as described above (step d). Compounds 6 in which V is xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 can be obtained by hydrogenation of compound 6 in EtOH with Pt2O.H2O (yields the saturated analogue 6) or by selective hydrogenation with other known methods (yields the double bond analogue 6). Optionally, the hydrogenation described above can be performed at an earlier stage e.g. the alcohol 16a or mesylate 17.
Alternatively, the group A1A2NC(A3A4C)L-acetylene can be synthesised by known methods and attached to compound 15a or 15b (Sonogashira-coupling), to yield the compounds of the present invention 6 (reaction step f).
Compounds of the formula 6 (n greater than 0) may be synthesised by Swern oxidation of the alcohol 3 (V=O and n greater than 0) to give the corresponding aldehyde 18 (step g) as an intermediate. The aldehyde 18 may be treated with triphenylphosphine, tetra-bromo-methane and triethylamine in CH2Cl2 at 0xc2x0 C. to RT to yield 2,2-Dibromo-vinyl derivative 19 (step h). Rearrangement with n-BuLi (ca 1.6 M in hexane) in THF at xe2x88x9278xc2x0 C., followed by reaction with formaldehyde (xe2x88x9278xc2x0 C. to RT) leads to the propargyl alcohol 20a (step i, side chain extension through application of the Corey-Fuchs method), following conditions described in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of the Pseudopterane (xe2x88x92)xe2x88x92Kallolide B, the Enantiomer of Natural (+)xe2x88x92Kallolide B. J. Org. Chem. (1996), 61(17), 5729-5735; and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415-21.
For longer side chains, the rearrangement is performed with n-BuLi (ca 1.6 M in hexane) in THF at xe2x88x9278xc2x0 C. as above, followed by addition of a co-solvens such as DMPU and reaction with O-protected 1-bromo-alcohols (e.g. 1-bromo-n-tetrahydro-pyaranyloxyalkane) to yield the O-protected compounds 20b (step i). O-protected compounds 20b can be deprotected to the corresponding alkynol 20a (in MeOH at 50-60xc2x0 C., in the presence of catalytic amount of pyridinium toluene-4-sulfonate). Alcohol 20a can be reacted with Huenig""s base/trifluoromethane sulfonic acid anhydride at xe2x88x9215xc2x0 C. in CH2Cl2 (in situ generation of the corresponding triflate) followed by treatment with Huenig""s base and the corresponding amine NHA1A2 at xe2x88x9215xc2x0 C. to RT to give amine 6. Alternatively, mesylation of alcohol 20a with methanesulfonylchloride, pyridine and DMAP in CH2Cl2 at 0xc2x0 C. to RT gives mesylate 21. Conversion of the mesylate 21 to the amine 6 can be accomplished with an excess of the corresponding amine NHA1A2 in DMA at RT or as described above (step l).
Compounds 6 in which V is xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 can be obtained by hydrogenation of compound 6 itself or the intermediates 20a, 20b or 21. The hydrogenation may be done in EtOH with Pt2Oxc2x7H2O (yields the saturated analogues 6, 20a, 20b, or 21) or by selective hydrogenation to the double bond with other known methods and transforming the intermediates afterwards to 5.
Alternatively, for the introduction of the group A1A2N(A3A4C)L in which A3 and/or A4 are not H, the following steps have to be performed starting from compound 19 (step m or steps i and l): for L=lower alkanes, the building block A1A2N(A3A4C)L-halogenide/mesylate is synthesised by known methods (or in analogy to the methods described in Scheme 2) and introduced (step m) under the same condition as described above for step i. For L=single bond, the introduction of the group A1A2N(A3A4C) with A3 and/or A4 not H, a two step procedure has to be followed: first the rearrangement of 19 with n-BuLi (ca 1.6 M in hexane) in THF at xe2x88x9278xc2x0 C., followed by reaction with the corresponding aldehyde (A3 or A4xe2x80x94COH) or ketone (A3COA4, at xe2x88x9278xc2x0 C. to RT) leads to the A3A4 substituted propargyl alcohol 20a (step i) which is e.g. mesylated or transformed to a phosphorester or a chloride (not shown) and reacted with the desired A1A2-substituted-amine in the presence of Tetrakis(triphenylphosphine)palladium (for the phosphorester) or Cu(I)Cl/Cu bronze and Huenig""s base (for the chloride) to yield the desired A3,A4-substituted compound 6 (step l). (see: Bartlett, Paul A.; McQuaid, Loretta A. Total synthesis of ()-methyl shikimate and ()-3-phosphoshikimic acid. J. Am. Chem. Soc. (1984), 106(25), 7854-60 and Cooper, Matthew A.; Lucas, Mathew A.; Taylor, Joanne M.; Ward, A. David; Williamson, Natalie M. A convenient method for the aromatic amino-Claisen rearrangement of N-(1,1-disubstituted-allyl)anilines. Synthesis (2001), (4), 621-625.)
For an amine 6 in which A7 is a halo-substituted aromatic system, the corresponding alkyne, alkyl, alkene, amine, alkoxy or thioalkoxy substituted derivative can be synthesized employing Sonogashira reaction or palladium catalyzed amination, Cxe2x80x94O or Cxe2x80x94S coupling reactions (as described for compound 3 in scheme 1) (or in case of a hydroxy substitution, the corresponding triflate may be synthesized).
If A2=H, heterocyclic moieties A2 maybe introduced by treatment with halo heterocycles in the presence of Huenig""s base in DMF (Ger. Offen. (1990), DE3905364 A1). Alternatively, Buchwald conditions e.g. Pd(OAc)2, 2-(Dicyclohexylphosphino) biphenyl, NaOtBu in toluene might be applied (John P. Wolfe, Hiroshi Tomori, Joseph P. Sadighi, Jingjun Yin, and Stephen L. Buchwald, J. Org. Chem., 65 (4), 1158-1174, 2000). For the preparation of oxazoline or thiaoxazolines the amine may be treated with chloroethylisocyanate or chloroethylthioisocyanate in THF, followed by treatment with a base such as triethylamine or ammonium hydroxide (George R. Brown, David M. Hollinshead, Elaine S. E. Stokes, David Waterson, David S. Clarke, Alan J. Foubister, Steven C. Glossop, Fergus McTaggart, Donald J. Mirrlees, Graham J. Smith, and Robin Wood Journal of Medicinal Chemistry, 2000, 43, 26, 4964-72.).
Furthermore, the indole moiety of amine 6 may be reduced to indoline 6 using a reducing agent such as sodium cyanoborohydride as described above (see scheme 1, step b).
Amine 6 may be converted to a salt or to the N-oxide 7 using a mixture of hydrogen peroxide urea adduct and phthalic anhydride in CH2Cl2 at RT (step e).
In the cases, in which a modification of A7 is envisaged to be done at the end of the synthesis, the synthesis might be carried out as described in scheme 3 with A7=PG. The protecting group can be cleaved under basic conditions like aqueous NaOH in an alkohol for the indole derivatives or by treatment with TFA in CH2Cl2 at RT or reflux for the indoline derivatives. Introduction of the moiety A7 may be accomplished as described in Scheme 1 for step a to give compound 6. Furthermore, a conversion of the indoline derivative to the indole compound is possible e.g. using a halobenzene in DMISO in the presence of K2CO3 and CuI at elevated temperature.
The following tests were carried out in order to determine the activity of the compounds of formula I and their salts.
Inhibition of Human Liver Microsomal 2,3-oxidosqualene-lanosterol Cyclase (OSC)
Liver microsomes from a healthy volunteer were prepared in sodium phosphate buffer (pH 7.4). The OSC activity was measured in the same buffer, which also contained 1 mM EDTA and 1 mM dithiothreitol. The microsomes were diluted to 0.8 mg/ml protein in cold phosphate buffer. Dry [14C]R,S-monooxidosqualene (MOS, 12.8 mCi/mmol) was diluted to 20 nCi/xcexcl with ethanol and mixed with phosphate buffer-1% BSA (bovine serum albumin). A stock solution of 1 mM test substance in DMSO was diluted to the desired concentration with phosphate buffer-1% BSA. 40 xcexcl of microsomes were mixed with 20 xcexcl of the solution of the test substance and the reaction was subsequently started with 20 xcexcl of the [14C]R,S-MOS solution. The final conditions were: 0.4 mg/ml of microsomal proteins and 30 xcexcl of [14C]R,S-MOS in phosphate buffer, pH 7.4, containing 0.5% albumin, DMSO  less than 0.1% and ethanol  less than 2%, in a total volume of 80 xcexcl.
After 1 hour at 37xc2x0 C. the reaction was stopped by the addition of 0.6 ml of 10% potassium hydroxide-methanol, 0.7ml of water and 0.1 ml of hexane:ether (1:1, v/v) which contained 25 xcexcg of non-radioactive MOS and 25 xcexcg of lanosterol as carriers. After shaking, 1 ml of hexane:ether (1:1, v/v) was added to each test tube, these were again shaken and then centrifuged. The upper phase was transferred into a glass test tube, the lower phase was again extracted with hexane:ether and combined with the first extract. The entire extract was evaporated to dryness with nitrogen, the residue was suspended in 50 xcexcl of hexane:ether and applied to a silica gel plate. Chromatographic separation was effected in hexane:ether (1:1, v/v) as the eluent. The Rf values for the MOS substrate and the lanosterol product were 0.91 and, respectively, 0.54. After drying, radioactive MOS and lanosterol were observed on the silica gel plate. The ratio of MOS to lanosterol was determined from the radioactive bands in order to determine the yield of the reaction and OSC inhibition.
The test was carried out on the one hand with a constant test substance concentration of 100 nM and the percentage OSC inhibition against controls was calculated. The more preferred compounds of the present invention exhibit inhibitions larger than 50%. In addition, the test was carried out with different test substance concentrations and subsequently the IC50 value was calculated, i.e. the concentration required to reduce the conversion of MOS into lanosterol to 50% of the control value. The preferred compounds of the present invention exhibit IC50 values of 1 nM to 10 xcexcM, preferably of 1-100 nM.
The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable acid addition salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 50 mg to about 500 mg, comes into consideration for the prevention and control of topical and systemic infections by pathogenic fungi. For cholesterol lowering and treatment of impaired glucose tolerance and diabetes the daily dosage conveniently amounts to between 1 and 1000 mg, preferably 5 to 200 mg, for adult patients. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 5-200 mg, of a compound of formula I.
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.